There is a growing awareness that even subtle renal derangements that result in an impaired capacity to regulate sodium excretion at normotensive arterial pressure or in an excessive production of vasoconstrictor hormones for the level of sodium balance may be of cardinal significance in the development of hypertension. A model of particular interest is 2-kidney-l-clip (2KlC) hypertension because it provides an opportunity to evaluate how a kidney that has not been directly manipulated responds, adapts and, in particular, contributes to the elevations in .arterial pressure that occur as a consequence of renal arterial stenosis imposed on the other kidney. Accordingly, the long term aim of this proposal is to define and characterize the intrarenal derangements in renal microcirculatory dynamics and tubular reabsortive function that exist in the contralateral nonclipped kidney during development and maintenance of hypertension induced by renal arterial constriction of the opposite kidney. For this period of support, experiments will be focused on the identification of the early factors that are responsible for the initiation of the sequence of events that result in established hypertension. The 2Kl C Goldblatt hypertensive rat and rabbit models will be used and both in vivo and in vitro experiments will be performed. The in vivo experiments will focus on the temporal responses of the contralateral kidney and on the circulating and intrarenal hormonal influences that contribute to an enhanced proximal tubular reabsorption rate and on an increased sensitivity of the tubuloglomerular feedback mechanism. The in vitro experiments will utilize the blood perfused juxtamedullary nephron preparation that allows direct visualization of the pre and post glomerular arterial the glomeruli, and extensive segments of proximal and distal tubules. We will characterize the alterations in vascular dimensions and in vascular responsiveness to vasoactive stimuli both at hypertensive and normotensive perfusion pressures. Further in vitro studies will evaluate the changes in the Na+/H+ exchanger in isolated proximal tubule cells occurring in 2Kl C hypertension. The results should further our understanding of the role of the kidney in the pathophysiology of hypertension in this specific model, and also provide insight into possible primary renal derangements that may be involved in essential hypertension.